DESCRIPTION (As provided by the Applicant): The control and modulation of transmitter release is critical to brain function. Voltage-gated calcium channels allow the calcium entry that triggers transmitter release. These channels are common targets of modulation, often via activation of G protein coupled receptors, and this modulation represents a powerful mechanism of about . presynaptic modulation of transmitter release. The pathways mediating direct (membrane-delimited) modulation of calcium channels are well characterized and show remarkable voltage-dependence, but little is known about the relevance of this characteristic to transmitter release. Somatostatin (SOM) is a neuropeptide that has been shown to inhibit calcium current and is hypothesized to be a negative feedback modulator of Ach release from the parasympathetic nerve endings of the chick ciliary ganglion. This proposal describes experiments to examine the effects of SOM on transmitter release using cultured ciliary ganglion neurons, which synapse with each other in mass culture. Additionally, the physiological relevance of the voltage-dependence of these effects will be determined by studying SOM-modulation of transmitter release evoked by trains of action potentials. It is hypothesized that SOM will inhibit transmitter release and that this inhibition will be sensitive to stimulation frequency and cytoplasmic dialysis. Furthermore, exogenous SOM will be able to modulate transmitter release at all frequencies tested, but endogenous SOM will be released preferentially with high firing frequency, thus will modulate only transmitter released following bursts of high frequency nerve activity.